The use of sulfonamides (sulfa drugs) for treating bacterial infections is known. The Merk Veterinary Manual, sixth edition, 1986, pages 1540 through 1544, provides general background on these drugs. It is believed that sulfonamides are effective antibacterial agents because they competitively inhibit an enzymatic step (dihydropterate synthetase) wherein as para-aminobenzoic acid is incorporated into the synthesis of dihydrofolic acid (folic acid). Because folic acid synthesis is reduced, the level of tetrahydrofolic acid (folinic acid) formed from folic acid is also reduced. Folinic acid is an essential component of various coenzymes responsible for single carbon metabolism in cells. Thus, sulfonamides create a domino effect in the body that ultimately results in the suppression of protein synthesis, the impairment of metabolic processes, and an inhibition in the growth and multiplication of organisms that cannot utilize preformed folic acid. The effect is bacteriostatic and, in high concentrations, bactericidal.
2,4-Diaminopyrimidines, such as trimethoprim, are also known antimicrobial agents that have found utility in the treatment of various bacterial and protozoal infections. U.S. Pat. Nos. 2,909,522 and 3,021,332 are two references directed to the formation and use of 2,4-diaminopyrimidines. It is believed that these compounds act by inhibiting an enzyme that facilitates the conversion of folic acid to folinic acid and, thereby, interfering with the biosynthesis of nucleic acids and proteins in bacteria. Typically, 2,4-diaminopyrimidines have a high selectivity for inhibiting the folate synthesis in protozoal enzymes as opposed to folate coenzyme synthesis in host cells. Thus, 2,4diaminopyrimidines are widely used in veterinary antimicrobial compositions.
When sulfonamides are combined with 2,4-diaminopyrimidines, a synergistic antimicrobial effect is often obtained. Although the enhancement in antimicrobial activity is mutual, the 2,4-diaminopyrimidines are often referred to as sulphonamide potentiators. This synergistic antimicrobial activity is very effective against gram-positive and gram-negative bacterial pathogens. The Merk Veterinary Manual, sixth edition, 1986, pages 1544 through 1546, provides general background information on this drug combination.
It would be desirable to combine sulfonamides with 2,4-diaminopyrimidines in a stable palatable concentrate that could be effectively administered to animals via their drinking water, e.g., through the automatic water and Tank water systems utilized in livestock facilities. This type of administration is the most cost effective means of treating large animal populations. Other techniques, such as injection, directly administering tablets or fluids, and powder/food mixtures, have numerous drawbacks. Injection is time consuming, costly, and potentially hazardous because the needle can break off in the animal and/or create an infective injection site. Force feeding tablets and fluids directly to an animal is, minimally, a taxing chore. Mixing sulfonamide and 2,4-diaminopyrimidine powders into an animal's food creates a bad tasting mixture that the animal is less likely to ingest, making it difficult to insure that even dosages are administered.
Unfortunately, 2,4-diaminopyrimidines and many sulfonamides exhibit poor solubility in water. Although techniques exist to increase the solubility of each compound individually, these techniques are incompatible. Sulfonamides are solubilized in water by the addition of a pharmaceutically acceptable inorganic base whereas 2,4-diaminopyrimidines are solubilized in water by the addition of a pharmaceutically acceptable acid. If the acidic and basic solutions are mixed, the sulfonamide and 2,4-diaminopyrimidine components precipitate out of solution.
Furthermore, in aqueous compositions where the pH approaches 7.0, sulfonamides and 2,4-diaminopyrimidines combine, in a 1 to 1 molar ratio, to form an insoluble and undesirable complex. Given that city water generally has a pH between 7.0 and 7.5, the formation of this complex is hard to avoid when the two compounds are placed into automatic or Tank water systems.
Attempts have been made to generate aqueous solutions containing both sulfonamides and 2,4-diaminopyrimidines by adding various types of water-miscible organic solvents, such as dimethylacetamide and low molecular weight polyalkylene glycols. U.S. Pat. Nos. 3,985,876, 4,031,214, and 4,089,949 are representative of this art. These solutions, which are primarily utilized in injection procedures, are not suitable for use in automatic water and Tank water facilities. The organic solvent's ability to promote solubility is quickly diminished by large scale dilution in water. Furthermore, large scale dilution in water typically brings the pH near 7.0, which is often outside the pH parameters necessary to maintain the solutions.
Compositions containing sulfonamides in solution and 2,4-diaminopyrimidine potentiators in suspension have also been made. U.S. Pat. Nos. 4,031,214 and 4,332,796 are representative of this art.
U.S. Pat. No. 4,031,214 describes an injectable preparation that comprises a suspension of finely divided potentiator within an aqueous solution containing a pharmaceutically acceptable water soluble salt of a sulphonamide and a strong base. The term potentiator is defined in the patent to include many types of 2,4-diaminopyrimidines. The pH of the preparation is stated to be at least 10 to avoid the growth of crystalline complexes. U.S. Pat. No. 4,031,214 does not disclose that the composition can be orally administered either directly or through drinking water. Furthermore, the patent does not disclose a suspending agent. Finally, it is clear from the pH parameters required in the patent that the composition described therein would not be useful in livestock drinking water where the pH typically approaches 7.0.
U.S. Pat. No. 4,332,796 describes potentiated sulfonamide compositions useful for intramuscular injection. The compositions comprise mixtures of alkali metal sulfonamides with microcrystalline potentiators wherein the microcrystals have been coated with mixtures of phospholipids and non-ionic surfactants. The compositions are alleged to be advantageous because they can be used for injection with the addition of sterile water. Furthermore, it is alleged that the resulting aqueous preparations are stable for long periods of time. The potentiator component preferably belongs to the 2,4-diaminopyrimidine class of compounds. The injectable mixture, with sterile water, has a pH in the advantageous range of 8.5-9.5. U.S. Pat. No. 4,332,796 does not disclose that the composition can be orally administered either directly or through drinking water. Furthermore, the patent does not disclose the use of a suspending agent. In fact, the reference teaches that suspending agents are undesirable because they provoke irritation at the injection site, lower chemotherapeutic diffusion in tissues and a decrease in injectability. Finally, it is clear from the high pH parameters required by the patent that the composition described therein would not be useful in livestock drinking water where the pH typically approaches 7.0.
Thus, there remains a need in the art for an antimicrobial concentrate that comprises a sulfonamide and/or salt thereof in combination with a diaminopyrimidine that may be orally administered to animals via their drinking water. To be economically feasible, the concentrate would have a room temperature shelf life of at least several days. In addition, when the concentrate is diluted in sufficient water to bring the pH near 7.0, the components in the concentrate would have to remain dissolved and/or suspended for at least a day.